Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the
most prevalent forms of the chronic and progressive pathological condition known as
cardiomyopathy. These diseases have different aetiologies; however, they share the feature of
haemodynamic abnormalities which is mainly due to dysfunction in the contractile proteins that
make up the contractile unit known as the sarcomere. To date, pharmacological treatment options
are not disease-specific and rather focus on managing the symptoms without addressing the disease
mechanism. Earliest attempts at improving cardiac contractility by modulating the sarcomere
indirectly (inotropes) resulting in unwanted effects. In contrast, targeting the sarcomere directly,
aided by high throughput screening systems, could identify small molecules with a superior
therapeutic value in cardiac muscle disorders. Here in, an extensive literature review of 21 small
molecules directed to five different targets was conducted. A simple scoring system was created to
assess the suitability of small molecules for therapy by evaluating them in 8 different criteria. Most
of the compounds failed due to lack of target specificity or poor physicochemical properties. Six
compounds stood out showing a potential therapeutic value in HCM, DCM or HF. Omecamtiv
Mecarbil and Danicamtiv (myosin activators), Mavacamten, CK-274 and MYK-581 (myosin
inhibitors) and AMG 594 (Ca2+-sensitiser) all are small molecules that allosterically modulate
troponin or myosin. Omecamtiv Mecarbil is currently under phase III trials for heart failure, while
results from phase III EXPLORER-HCM trial were recently published indicating that Mavacamten
reduced left ventricular outflow tract (LVOT) obstruction and diastolic dysfunction and improved
the health status of patients with HCM. A novel category of small molecules known as ‘Recouplers’
was reported to target a phenomenon termed uncoupling commonly found in familial
cardiomyopathies but has not progressed beyond preclinical work. In conclusion, the contractile
apparatus is a promising target for new drug development.